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Immune mechanisms that control the homeostasis of the gut and that are deregulated in intestinal pathologies cancer

Final Report Summary - HOMEOGUT (Immune mechanisms that control the homeostasis of the gut and that are deregulated in intestinal pathologies cancer.)

We have identified a new anatomical structure called the gut vascular barrier (GVB), which resembles the blood brain barrier. Our organism is equipped with a vascular barrier that controls what enters the brain so to avoid unnecessary inflammation. Similarly, in the gut we have a vascular barrier that controls what can enter the blood circulation and reach systemic sites of our organism such as the liver and the spleen.
This barrier ensures that even if bacteria, which colonize the gut (the microbiota), accidentally cross the epithelium, are excluded from reaching the whole body thus avoiding systemic infection. However, some bacteria such as Salmonella enterica can subvert this barrier to spread in the whole body and cause infection (the typhoid fevers). We found that the barrier is disrupted also in some patients suffering from liver damage secondary to celiac disease. We found that barrier is compromised also in non alcoholic steatohepatitis (NASH) and inflammatory bowel disease (IBD) patients as well as in murine model of these pathologies.
Finally, we have confirmed that the two TSLP isoforms have opposite functions; the long TSLP exacerbates inflammatory and allergic reactions while the short TSLP is constitutively expressed and anti-inflammatory. The short TSLP acts on dendritic cells decreasing their inflammatory potential and this translates in a protective effect in vivo in mice and ex-vivo on human tissues. In parallel, we have developed small synthetic peptides that inhibit the inflammatory activity of the total long TSLP. The interest of targeting TSLP has increased over the years with the goal of reducing inflammation of the airways and allergen sensitivity in asthma patients.